Crystal forms

ABSTRACT

The present invention features crystalline forms of Compound I. In one embodiment, a crystalline form of Compound I has characteristic peaks in the PXRD pattern as shown in one of FIGS.  1 - 10.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/991,242, filed May 9, 2014, the contents of which areincorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to crystalline polymorphs of Compound I,pharmaceutical compositions comprising the same, and methods of usingthe same to prepare pharmaceutical compositions.

BACKGROUND

The hepatitis C virus (HCV) is an RNA virus belonging to the Hepacivirusgenus in the Flaviviridae family. The enveloped HCV virion contains apositive stranded RNA genome encoding all known virus-specific proteinsin a single, uninterrupted, open reading frame. The open reading framecomprises approximately 9500 nucleotides and encodes a single largepolyprotein of about 3000 amino acids. The polyprotein comprises a coreprotein, envelope proteins E1 and E2, a membrane bound protein p7, andthe non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B.

HCV infection is associated with progressive liver pathology, includingcirrhosis and hepatocellular carcinoma. Chronic hepatitis C may betreated with peginterferon-alpha in combination with ribavirin.Substantial limitations to efficacy and tolerability remain as manyusers suffer from side effects, and viral elimination from the body isoften inadequate. Therefore, there is a need for new drugs to treat HCVinfection.

BRIEF DESCRIPTION OF THE DRAWINGS

The drawings are provided for illustration, not limitation.

FIG. 1 shows experimental PXRD patterns of Compound I n-butylamine-H2Osolvate (Pattern A or Form I).

FIG. 2 depicts experimental PXRD pattern of Compound I Pattern B.

FIG. 3 describes experimental PXRD of Compound I Pattern B (MeOH-Diethylether solvate).

FIG. 4 shows experimental PXRD of Compound I Pattern C (anhydrate).

FIG. 5 illustrates experimental PXRD of Compound I Pattern C (MTBEsolvate).

FIG. 6 depicts experimental PXRD of Compound I Pattern D (fromEtOH/H₂O).

FIG. 7 shows experimental PXRD of Compound I Pattern E (hydrate).

FIG. 8 describes experimental PXRD of Compound I ACN solvate (Pattern For Form II).

FIG. 9 shows experimental PXRD of Compound I anhydrate (Pattern G orForm III).

FIG. 10 depicts experimental PXRD of Compound I di-n-butyl ether solvate(Pattern H).

DETAILED DESCRIPTION

The present invention features crystalline polymorphs of methyl{(2S,3R)-1-[(2S)-2-{5-[(2R,5R)-1-{3,5-difluoro-4-[4-(4-fluorophenyl)piperidin-1-yl]phenyl}-5-(6-fluoro-2-{(2S)-1-[N-(methoxycarbonyl)-O-methyl-L-threonyl]pyrrolidin-2-yl}-1H-benzimidazol-5-yl)pyrrolidin-2-yl]-6-fluoro-1H-benzimidazol-2-yl}pyrrolidin-1-yl]-3-methoxy-1-oxobutan-2-yl}carbamate

herein “Compound I”). Compound I is a potent HCV NS5A inhibitor and isdescribed in U.S. Patent Application Publication No. 2012/0004196, whichis incorporated herein by reference in its entirety.

Compound I was found to be very difficult to crystallize during earlydevelopment. Crystalline Compound I was not readily obtained despitemonths of development work. Even if a crystalline form of Compound I hadbeen known to exit, the precise crystal structure of the crystallineform would generally not have been predictable.

A crystalline form of Compound I was unexpectedly obtained using ahighly unconventional solvent system—namely, n-butylamine. Additionalcrystalline forms were subsequently identified. Prior to the isolationand characterization of these crystalline forms, the existence andidentity of these particular polymorphs had not been expected. Thesecrystalline forms can be used to improve formulation (e.g., via hot meltextrusion), allow for purification via crystallization as well asmanufacturing at scale, and enable improved stability, handling and bulkproperties among others.

In one aspect, the invention features a crystalline form of Compound Iwhich has characteristic peaks in the powder X-ray diffraction (PXRD)pattern as shown in FIG. 1.

In another aspect, the invention features a crystalline form of CompoundI which has characteristic peaks in the powder X-ray diffraction (PXRD)pattern at values of two theta (° 2θ) as shown in Table 1.

The relative intensity, as well as the two theta value, of each peak inTables 1-10 and FIGS. 1-10 may change or shift under certain conditions,although the crystalline form is the same. One of ordinary skill in theart should be able to readily determine whether a given crystalline formis the same crystalline form as described in one of FIGS. 1-10 or Tables1-10 by comparing their PXRD profiles.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.78, 4.09,8.19, 9.15, 10.42, 13.02, 13.50, 18.45, 19.48, and 20.86.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.78, 4.09,6.92, 8.19, 9.15, 10.12, 10.42, 12.30, 13.02, 13.50, 14.77, 16.20,16.97, 18.12, 18.45, 19.48, 20.86, 24.24, 24.79, and 25.97.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.78, 4.09,6.72, 6.92, 8.19, 9.15, 9.84, 10.12, 10.42, 10.72, 11.66, 12.30, 13.02,13.50, 14.77, 15.26, 15.62, 16.20, 16.97, 17.27, 17.55, 18.12, 18.45,19.48, 19.90, 20.37, 20.61, 20.86, 21.99, 22.25, 22.72, 24.24, 24.79,25.97, 26.88, 27.42, 27.81, and 30.23.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 2.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 2.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.70, 7.53,10.51, 11.43, 11.80, 15.85, 17.23, 19.11, 21.37, and 23.00.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.23, 5.70,7.53, 8.24, 8.97, 10.51, 11.43, 11.80, 12.05, 12.69, 13.23, 14.97,15.85, 17.23, 19.11, 20.20, 21.37, 21.99, 22.22, and 23.00.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.23, 5.70,7.53, 8.24, 8.97, 10.51, 11.43, 11.80, 12.05, 12.69, 13.23, 13.99,14.97, 15.85, 17.23, 18.45, 19.11, 19.76, 20.20, 21.37, 21.99, 22.22,23.00, 25.17, 25.43, 26.73, and 32.46.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 3.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 3.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.22, 5.69,7.55, 10.49, 11.38, 11.84, 15.99, 17.23, 19.18, and 21.41.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.22, 5.69,7.55, 8.21, 9.40, 10.49, 11.38, 11.84, 12.04, 12.67, 13.24, 15.99,17.23, 19.18, 20.15, 21.41, 22.10, 22.53, 23.02, and 25.19.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.22, 5.69,7.55, 8.21, 8.99, 9.40, 10.49, 11.07, 11.38, 11.84, 12.04, 12.67, 13.24,13.99, 14.96, 15.99, 17.23, 18.10, 18.47, 19.18, 20.15, 21.41, 22.10,22.53, 23.02, 25.19, 25.69, 26.57, 26.98, 30.09, and 32.45.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 4.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 4.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.43, 6.24,7.53, 10.91, 12.34, 12.57, 13.67, 13.94, 17.44, and 19.30.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.43, 6.24,7.53, 8.68, 10.58, 10.91, 12.34, 12.57, 13.67, 13.94, 14.71, 15.40,15.99, 16.64, 17.44, 19.30, 19.70, 21.10, 21.33, and 21.72.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.43, 6.24,7.53, 8.68, 9.28, 10.58, 10.91, 11.65, 12.34, 12.57, 13.67, 13.94,14.71, 15.40, 15.99, 16.64, 17.44, 19.30, 19.70, 21.10, 21.33, 21.72,and 22.78.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 5.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 5.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.57, 6.19,7.50, 10.86, 11.46, 12.42, 13.59, 15.28, 16.66, and 19.44.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.57, 6.19,7.50, 8.75, 10.86, 11.08, 11.46, 12.42, 13.59, 15.28, 16.26, 16.66,17.25, 17.87, 19.44, 20.80, 21.13, 21.39, 22.15, and 27.12.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.57, 6.19,7.50, 8.75, 10.86, 11.08, 11.46, 12.42, 12.84, 13.59, 15.28, 16.26,16.66, 17.25, 17.87, 19.44, 20.80, 21.13, 21.39, 22.15, 23.17, 24.15,and 27.12.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 6.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 6.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 4.35, 4.68,7.33, 12.01, 13.13, 13.35, 16.54, 17.96, 18.26, and 21.21.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 4.35, 4.68,6.41, 7.33, 9.54, 10.26, 11.13, 11.34, 12.01, 13.13, 13.35, 14.33,16.54, 17.96, 18.26, 18.60, 19.77, 21.21, 21.75, and 24.19.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 4.35, 4.68,6.41, 6.92, 7.33, 9.25, 9.54, 10.26, 11.13, 11.34, 12.01, 13.13, 13.35,14.33, 14.65, 15.36, 16.54, 17.96, 18.26, 18.60, 19.05, 19.77, 21.21,21.75, and 24.19.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 7.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 7.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.36, 8.81,10.09, 10.69, 11.43, 12.95, 14.14, 17.96, 18.28, and 22.88.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.50, 5.36,8.81, 10.09, 10.69, 11.43, 12.19, 12.95, 14.14, 14.72, 15.18, 17.53,17.96, 18.28, 18.86, 21.36, 22.01, 22.88, 26.54, and 28.04.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.50, 4.61,5.36, 5.79, 7.61, 8.81, 10.09, 10.69, 11.43, 12.19, 12.95, 14.14, 14.72,15.18, 15.64, 16.87, 17.53, 17.96, 18.28, 18.86, 19.76, 21.36, 22.01,22.88, 24.42, 25.20, 26.54, 28.04, and 28.65.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 8.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 8.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.08, 10.81,12.05, 13.47, 13.68, 17.68, 19.02, 19.48, 21.73, and 25.53.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.08, 7.82,10.27, 10.81, 12.05, 13.47, 13.68, 14.95, 16.81, 17.68, 19.02, 19.48,20.36, 21.73, 22.24, 23.48, 25.53, 26.93, 32.01, and 33.12.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.08, 7.82,10.27, 10.81, 11.11, 12.05, 13.47, 13.68, 14.95, 15.57, 16.28, 16.81,17.68, 19.02, 19.48, 20.36, 21.73, 22.24, 23.48, 24.16, 25.53, 26.93,28.26, 30.41, 31.07, 32.01, 33.12, and 35.04.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 9.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 9.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.31, 11.11,12.60, 13.75, 15.29, 15.96, 17.62, 19.71, 21.30, and 22.88.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.31, 10.16,10.62, 11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71,20.58, 21.30, 22.40, 22.88, 23.66, 26.40, 26.74, and 33.46.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.31, 10.16,10.62, 11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71,20.58, 21.30, 22.40, 22.88, 23.66, 26.40, 26.74, 28.12, 31.62, and33.46.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 10.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 10.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 7.42, 10.57,11.84, 13.74, 15.72, 17.36, 19.38, 21.34, 22.07, and 23.36.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.28, 5.65,7.42, 9.26, 10.57, 10.90, 11.31, 11.84, 12.15, 12.73, 13.74, 15.72,17.36, 18.04, 19.38, 21.34, 22.07, 22.90, 23.36, and 26.49.

In yet another aspect, the invention features a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.28, 5.65,7.42, 8.02, 8.94, 9.26, 10.57, 10.90, 11.31, 11.84, 12.15, 12.73, 13.14,13.74, 14.78, 15.72, 16.32, 16.95, 17.36, 18.04, 18.81, 19.38, 21.34,22.07, 22.90, 23.36, 24.50, 25.13, 25.59, 26.49, 32.24, and 32.93.

As used herein, PXRD data can be collected using a G3000 diffractometer(Inel Corp., Artenay, France) equipped with a curved position-sensitivedetector and parallel-beam optics. The diffractometer is operated with acopper anode tube (1.5 kW fine focus) at 40 kV and 30 mA. Anincident-beam germanium monochromator provides monochromatic Cu-K_(α)radiation, which has a wavelength of 1.54178 Å. The diffractometer iscalibrated using the attenuated direct beam at one-degree intervals.Calibration is checked using a silicon powder line position referencestandard (NIST 640c). The instrument is computer-controlled usingSymphonix software (Inel Corp., Artenay, France) and the data areanalyzed using Jade software (version 6.5, Materials Data, Inc.,Livermore, Calif.). The sample can be loaded onto an aluminum sampleholder and leveled with a glass slide. PXRD peak position measurementsare typically ±0.2 degrees two-theta (° 2θ).

In another aspect, the present invention features a crystalline formdescribed above which is substantially pure. As used herein, the term“substantially pure”, when used in reference to a given crystallineform, refers to the crystalline form which is at least about 90% pure.This means that the crystalline form does not contain more than about10% of any other form of Compound I. More preferably, the term“substantially pure” refers to a crystalline form of Compound I which isat least about 95% pure. This means that the crystalline form ofCompound I does not contain more than about 5% of any other form ofCompound I. Even more preferably, the term “substantially pure” refersto a crystalline form of Compound I which is at least about 97% pure.This means that the crystalline form of Compound I does not contain morethan about 3% of any other form of Compound I.

In one embodiment, the present invention feature a crystalline form ofCompound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 1 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 1 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.78, 4.09,8.19, 9.15, 10.42, 13.02, 13.50, 18.45, 19.48, and 20.86, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.78, 4.09,6.92, 8.19, 9.15, 10.12, 10.42, 12.30, 13.02, 13.50, 14.77, 16.20,16.97, 18.12, 18.45, 19.48, 20.86, 24.24, 24.79, and 25.97, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.78, 4.09,6.72, 6.92, 8.19, 9.15, 9.84, 10.12, 10.42, 10.72, 11.66, 12.30, 13.02,13.50, 14.77, 15.26, 15.62, 16.20, 16.97, 17.27, 17.55, 18.12, 18.45,19.48, 19.90, 20.37, 20.61, 20.86, 21.99, 22.25, 22.72, 24.24, 24.79,25.97, 26.88, 27.42, 27.81, and 30.23, and which is substantially pure.For example the crystalline form can be at least 90% pure, preferably atleast 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 2 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 2 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.70, 7.53,10.51, 11.43, 11.80, 15.85, 17.23, 19.11, 21.37, and 23.00, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.23, 5.70,7.53, 8.24, 8.97, 10.51, 11.43, 11.80, 12.05, 12.69, 13.23, 14.97,15.85, 17.23, 19.11, 20.20, 21.37, 21.99, 22.22, and 23.00, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.23, 5.70,7.53, 8.24, 8.97, 10.51, 11.43, 11.80, 12.05, 12.69, 13.23, 13.99,14.97, 15.85, 17.23, 18.45, 19.11, 19.76, 20.20, 21.37, 21.99, 22.22,23.00, 25.17, 25.43, 26.73, and 32.46, and which is substantially pure.For example the crystalline form can be at least 90% pure, preferably atleast 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 3 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 3 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.22, 5.69,7.55, 10.49, 11.38, 11.84, 15.99, 17.23, 19.18, and 21.41, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.22, 5.69,7.55, 8.21, 9.40, 10.49, 11.38, 11.84, 12.04, 12.67, 13.24, 15.99,17.23, 19.18, 20.15, 21.41, 22.10, 22.53, 23.02, and 25.19, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.22, 5.69,7.55, 8.21, 8.99, 9.40, 10.49, 11.07, 11.38, 11.84, 12.04, 12.67, 13.24,13.99, 14.96, 15.99, 17.23, 18.10, 18.47, 19.18, 20.15, 21.41, 22.10,22.53, 23.02, 25.19, 25.69, 26.57, 26.98, 30.09, and 32.45, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 4 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 4 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.43, 6.24,7.53, 10.91, 12.34, 12.57, 13.67, 13.94, 17.44, and 19.30, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.43, 6.24,7.53, 8.68, 10.58, 10.91, 12.34, 12.57, 13.67, 13.94, 14.71, 15.40,15.99, 16.64, 17.44, 19.30, 19.70, 21.10, 21.33, and 21.72, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.43, 6.24,7.53, 8.68, 9.28, 10.58, 10.91, 11.65, 12.34, 12.57, 13.67, 13.94,14.71, 15.40, 15.99, 16.64, 17.44, 19.30, 19.70, 21.10, 21.33, 21.72,and 22.78, and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 5 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 5 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.57, 6.19,7.50, 10.86, 11.46, 12.42, 13.59, 15.28, 16.66, and 19.44, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.57, 6.19,7.50, 8.75, 10.86, 11.08, 11.46, 12.42, 13.59, 15.28, 16.26, 16.66,17.25, 17.87, 19.44, 20.80, 21.13, 21.39, 22.15, and 27.12, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.57, 6.19,7.50, 8.75, 10.86, 11.08, 11.46, 12.42, 12.84, 13.59, 15.28, 16.26,16.66, 17.25, 17.87, 19.44, 20.80, 21.13, 21.39, 22.15, 23.17, 24.15,and 27.12, and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 6 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 6 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 4.35, 4.68,7.33, 12.01, 13.13, 13.35, 16.54, 17.96, 18.26, and 21.21, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 4.35, 4.68,6.41, 7.33, 9.54, 10.26, 11.13, 11.34, 12.01, 13.13, 13.35, 14.33,16.54, 17.96, 18.26, 18.60, 19.77, 21.21, 21.75, and 24.19, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 4.35, 4.68,6.41, 6.92, 7.33, 9.25, 9.54, 10.26, 11.13, 11.34, 12.01, 13.13, 13.35,14.33, 14.65, 15.36, 16.54, 17.96, 18.26, 18.60, 19.05, 19.77, 21.21,21.75, and 24.19, and which is substantially pure. For example thecrystalline form can be at least 90% pure, preferably at least 95% pure,or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 7 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 7 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.36, 8.81,10.09, 10.69, 11.43, 12.95, 14.14, 17.96, 18.28, and 22.88, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.50, 5.36,8.81, 10.09, 10.69, 11.43, 12.19, 12.95, 14.14, 14.72, 15.18, 17.53,17.96, 18.28, 18.86, 21.36, 22.01, 22.88, 26.54, and 28.04, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 3.50, 4.61,5.36, 5.79, 7.61, 8.81, 10.09, 10.69, 11.43, 12.19, 12.95, 14.14, 14.72,15.18, 15.64, 16.87, 17.53, 17.96, 18.28, 18.86, 19.76, 21.36, 22.01,22.88, 24.42, 25.20, 26.54, 28.04, and 28.65, and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 8 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 8 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.08, 10.81,12.05, 13.47, 13.68, 17.68, 19.02, 19.48, 21.73, and 25.53, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.08, 7.82,10.27, 10.81, 12.05, 13.47, 13.68, 14.95, 16.81, 17.68, 19.02, 19.48,20.36, 21.73, 22.24, 23.48, 25.53, 26.93, 32.01, and 33.12, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.08, 7.82,10.27, 10.81, 11.11, 12.05, 13.47, 13.68, 14.95, 15.57, 16.28, 16.81,17.68, 19.02, 19.48, 20.36, 21.73, 22.24, 23.48, 24.16, 25.53, 26.93,28.26, 30.41, 31.07, 32.01, 33.12, and 35.04, and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 9 and which is substantiallypure. For example the crystalline form can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 9 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.31, 11.11,12.60, 13.75, 15.29, 15.96, 17.62, 19.71, 21.30, and 22.88, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.31, 10.16,10.62, 11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71,20.58, 21.30, 22.40, 22.88, 23.66, 26.40, 26.74, and 33.46, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.31, 10.16,10.62, 11.11, 12.60, 13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71,20.58, 21.30, 22.40, 22.88, 23.66, 26.40, 26.74, 28.12, 31.62, and33.46, and which is substantially pure. For example the crystalline formcan be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern as shown in FIG. 10 and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, the present invention feature a crystallineform of Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) as shown inTable 10 and which is substantially pure. For example the crystallineform can be at least 90% pure, preferably at least 95% pure, or morepreferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 7.42, 10.57,11.84, 13.74, 15.72, 17.36, 19.38, 21.34, 22.07, and 23.36, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.28, 5.65,7.42, 9.26, 10.57, 10.90, 11.31, 11.84, 12.15, 12.73, 13.74, 15.72,17.36, 18.04, 19.38, 21.34, 22.07, 22.90, 23.36, and 26.49, and which issubstantially pure. For example the crystalline form can be at least 90%pure, preferably at least 95% pure, or more preferably at least 97%.

In another embodiment, the present invention feature a crystalline formof Compound I which has characteristic peaks in the powder X-raydiffraction (PXRD) pattern at values of two theta (° 2θ) of 5.28, 5.65,7.42, 8.02, 8.94, 9.26, 10.57, 10.90, 11.31, 11.84, 12.15, 12.73, 13.14,13.74, 14.78, 15.72, 16.32, 16.95, 17.36, 18.04, 18.81, 19.38, 21.34,22.07, 22.90, 23.36, 24.50, 25.13, 25.59, 26.49, 32.24, and 32.93, andwhich is substantially pure. For example the crystalline form can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In yet another aspect, the present invention features processes of usinga crystalline form of the invention to make a composition comprisingCompound I. The processes comprise dissolving a crystalline form of theinvention in a solvent.

Any crystalline form described herein, including any crystalline formdescribed in any aspect, embodiment or example of this application, canbe used in any process of the invention described herein.

In one embodiment, the solvent is a volatile solvent such as ethanol ormethanol. A suitable excipient, such as a hydrophilic polymer describedbelow or a sugar alcohol, can also be dissolved in the solvent. Thesolution thus produced can then be dried to remove the solvent, such asvia spray drying, freeze drying or other solvent evaporizationtechniques, thereby creating a solid dispersion that comprises CompoundI and the excipient. Preferably, Compound I is in an amorphous form inthe solid dispersion. More preferably, the solid dispersion is a solidsolution or a glassy solution. In many cases, a pharmaceuticallyacceptable surfactant described below can also be added to the solutionprior to solvent removal; and as a result, the solid dispersion/solidsolution/glass solution produced according to this embodiment alsocomprises the surfactant.

In another embodiment, the solvent is an excipient, such as ahydrophilic polymer described below or a sugar alcohol, in a molten orrubbery state. The crystalline form of Compound I dissolves in themolten or rubbery excipient. Heating may be used to facilitate thedissolving and mixing of the crystalline form of Compound I in themolten or rubbery excipient. Preferably, melt extrusion is used todissolve and mix the crystalline form of Compound I in the excipient. Asolution or melt thus produced can be cooled and solidified to form asolid dispersion that comprises Compound I and the excipient.Preferably, Compound I is in an amorphous form in the solid dispersion.More preferably, the solid dispersion is a solid solution or a glassysolution. The solid dispersion, solid solution or glassy solution can bemilled, ground or granulated, and then compressed into a tablet oranother suitable solid dosage form with or without other additives. Thesolid dispersion, solid solution or glassy solution can also be directlyshaped or configured into a tablet or another suitable solid dosageform. In many cases, a pharmaceutically acceptable surfactant describedbelow can be added to the solution or melt prior to solidification; andas a result, the solid dispersion/solid solution/glassy solutionproduced according to this embodiment also comprises the surfactant.

In yet another embodiment, both heating and a volatile solvent are usedto dissolve a crystalline form of Compound I in a solution comprising asuitable excipient.

As used herein, the term “solid dispersion” defines a system in a solidstate (as opposed to a liquid or gaseous state) comprising at least twocomponents, wherein one component is dispersed throughout the othercomponent or components. For example, an active ingredient or acombination of active ingredients can be dispersed in a matrix comprisedof a pharmaceutically acceptable hydrophilic polymer(s) and apharmaceutically acceptable surfactant(s). The term “solid dispersion”encompasses systems having small particles of one phase dispersed inanother phase. When a solid dispersion of the components is such thatthe system is chemically and physically uniform or homogenous throughoutor consists of one phase (as defined in thermodynamics), such a soliddispersion is called a “solid solution.” A glassy solution is a solidsolution in which a solute is dissolved in a glassy solvent.

Non-limiting examples of excipients suitable for use in a process of theinvention include numerous hydrophilic polymers. Preferably, ahydrophilic polymer employed in a process of the invention has a T_(g)of at least 50° C., more preferably at least 60° C., and highlypreferably at least 80° C. including, but not limited to from, 80° C. to180° C., or from 100° C. to 150° C. Methods for determining T_(g) valuesof organic polymers are described in INTRODUCTION TO PHYSICAL POLYMERSCIENCE (2nd Edition by L. H. Sperling, published by John Wiley & Sons,Inc., 1992). The T_(g) value can be calculated as the weighted sum ofthe T_(g) values for homopolymers derived from each of the individualmonomers, i.e., the polymer T_(g)=ΣW_(i)·X_(i) where W_(i) is the weightpercent of monomer i in the organic polymer, and X, is the T_(g) valuefor the homopolymer derived from monomer i. T_(g) values for thehomopolymers may be taken from POLYMER HANDBOOK (2nd Edition by J.Brandrup and E. H. Immergut, Editors, published by John Wiley & Sons,Inc., 1975). Hydrophilic polymers with a T_(g) as described above mayallow for the preparation of solid dispersions that are mechanicallystable and, within ordinary temperature ranges, sufficiently temperaturestable so that the solid dispersions may be used as dosage forms withoutfurther processing or be compacted to tablets with only a small amountof tabletting aids. Hydrophilic polymers having a T_(g) of below 50° C.may also be used.

Preferably, a hydrophilic polymer employed in the present invention iswater-soluble. A solid composition of the present invention can alsocomprise poorly water-soluble or water-insoluble polymer or polymers,such as cross-linked polymers. A hydrophilic polymer comprised in asolid composition of the present invention preferably has an apparentviscosity, when dissolved at 20° C. in an aqueous solution at 2% (w/v),of 1 to 5000 mPa·s., and more preferably of 1 to 700 mPa·s, and mostpreferably of 5 to 100 mPa·s.

Hydrophilic polymers suitable for use in a process of the inventioninclude, but are not limited to, homopolymers or copolymers of N-vinyllactams, such as homopolymers or copolymers of N-vinyl pyrrolidone(e.g., polyvinylpyrrolidone (PVP), or copolymers of N-vinyl pyrrolidoneand vinyl acetate or vinyl propionate); cellulose esters or celluloseethers, such as alkylcelluloses (e.g., methylcellulose orethylcellulose), hydroxyalkylcelluloses (e.g., hydroxypropylcellulose),hydroxyalkylalkylcelluloses (e.g., hydroxypropylmethylcellulose), andcellulose phthalates or succinates (e.g., cellulose acetate phthalateand hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulosesuccinate, or hydroxypropylmethylcellulose acetate succinate); highmolecular polyalkylene oxides, such as polyethylene oxide, polypropyleneoxide, and copolymers of ethylene oxide and propylene oxide;polyacrylates or polymethacrylates, such as methacrylic acid/ethylacrylate copolymers, methacrylic acid/methyl methacrylate copolymers,butyl methacrylate/2-dimethylaminoethyl methacrylate copolymers,poly(hydroxyalkyl acrylates), and poly(hydroxyalkyl methacrylates);polyacrylamides; vinyl acetate polymers, such as copolymers of vinylacetate and crotonic acid, and partially hydrolyzed polyvinyl acetate(also referred to as partially saponified “polyvinyl alcohol”);polyvinyl alcohol; oligo- or polysaccharides, such as carrageenans,galactomannans, and xanthan gum; polyhydroxyalkylacrylates;polyhydroxyalkyl-methacrylates; copolymers of methyl methacrylate andacrylic acid; polyethylene glycols (PEGs); or any mixture thereof.

Non-limiting examples of preferred hydrophilic polymers for use in aprocess of the invention include polyvinylpyrrolidone (PVP) K17, PVPK25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3, HPMC E5,HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate(AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG,HPMC phthalate (P) 50, HPMC P 55, Ethocel 4, Ethocel 7, Ethocel 10,Ethocel 14, Ethocel 20, copovidone (vinylpyrrolidone-vinyl acetatecopolymer 60/40), polyvinyl acetate, methacrylate/methacrylic acidcopolymer (Eudragit) L100-55, Eudragit L100, Eudragit S100, polyethyleneglycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG8000, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, andpoloxamer 407.

Of these, homopolymers or copolymers of N-vinyl pyrrolidone, such ascopolymers of N-vinyl pyrrolidone and vinyl acetate, are preferred. Anon-limiting example of a preferred polymer is a copolymer of 60% byweight of N-vinyl pyrrolidone and 40% by weight of vinyl acetate. Otherpreferred polymers include, without limitation, hydroxypropylmethylcellulose (HPMC, also known as hypromellose in USP), such ashydroxypropyl methylcellulose grade E5 (HPMC-E5); and hydroxypropylmethylcellulose acetate succinate (HPMC-AS).

A pharmaceutically acceptable surfactant employed in a process of theinvention is preferably a non-ionic surfactant. More preferably, thenon-ionic surfactant has an HLB value of from 2-20. The HLB system(Fiedler, H. B., ENCYLOPEDIA OF EXCIPIENTS, 5^(th) ed., Aulendorf:ECV-Editio-Cantor-Verlag (2002)) attributes numeric values tosurfactants, with lipophilic substances receiving lower HLB values andhydrophilic substances receiving higher HLB values.

Non-limiting examples of pharmaceutically acceptable surfactants thatare suitable for use in a process of the invention includepolyoxyethylene castor oil derivates, e.g. polyoxyethyleneglyceroltriricinoleate or polyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) orpolyoxyethyleneglycerol oxystearate such as polyethylenglycol 40hydrogenated castor oil (Cremophor® RH 40, also known as polyoxyl 40hydrogenated castor oil or macrogolglycerol hydroxystearate) orpolyethylenglycol 60 hydrogenated castor oil (Cremophor® RH 60); or amono fatty acid ester of polyoxyethylene sorbitan, such as a mono fattyacid ester of polyoxyethylene (20) sorbitan, e.g. polyoxyethylene (20)sorbitan monooleate (Tween® 80), polyoxyethylene (20) sorbitanmonostearate (Tween® 60), polyoxyethylene (20) sorbitan monopalmitate(Tween® 40), or polyoxyethylene (20) sorbitan monolaurate (Tween® 20).Other non-limiting examples of suitable surfactants includepolyoxyethylene alkyl ethers, e.g. polyoxyethylene (3) lauryl ether,polyoxyethylene (5) cetyl ether, polyoxyethylene (2) stearyl ether,polyoxyethylene (5) stearyl ether; polyoxyethylene alkylaryl ethers,e.g. polyoxyethylene (2) nonylphenyl ether, polyoxyethylene (3)nonylphenyl ether, polyoxyethylene (4) nonylphenyl ether,polyoxyethylene (3) octylphenyl ether; polyethylene glycol fatty acidesters, e.g. PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate,PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate; alkylene glycolfatty acid mono esters, e.g. propylene glycol monolaurate(Lauroglycol®); sucrose fatty acid esters, e.g. sucrose monostearate,sucrose distearate, sucrose monolaurate, sucrose dilaurate; sorbitanfatty acid mono esters such as sorbitan mono laurate (Span® 20),sorbitan monooleate, sorbitan monopalnitate (Span® 40), or sorbitanstearate. Other suitable surfactants include, but are not limited to,block copolymers of ethylene oxide and propylene oxide, also known aspolyoxyethylene polyoxypropylene block copolymers or polyoxyethylenepolypropyleneglycol, such as Poloxamer® 124, Poloxamer® 188, Poloxamer®237, Poloxamer® 388, or Poloxamer® 407 (BASF Wyandotte Corp.).

Non-limiting examples of preferred surfactants for use in a process ofthe invention include polysorbate 20, polysorbate 40, polysorbate 60,polysorbate 80, Cremophor RH 40, Cremophor EL, Gelucire 44/14, Gelucire50/13, D-alpha-tocopheryl polyethylene glycol 1000 succinate (vitamin ETPGS), propylene glycol laurate, sodium lauryl sulfate, and sorbitanmonolaurate.

A pharmaceutically acceptable surfactant as used herein can be a mixtureof pharmaceutically acceptable surfactants, such as a combination of asurfactant having an HLB value of below 10 and another surfactant havingan HLB value of no lees than 10.

In one embodiment, a surfactant having an HLB value of at least 10 isused in a process of the invention. In another embodiment, a surfactanthaving an HLB value of below 10 is used in a process of the invention.In yet another embodiment, a mixture of two or more surfactants (e.g., acombination of one surfactant having an HLB value of at least 10 andanother surfactant having an HLB value of below 10) is used in a processof the invention.

In one embodiment, a process of the invention comprises dissolving acrystalline form of the invention, a hydrophilic polymer describedabove, and a surfactant described above to form a solution (e.g., amelt). The hydrophilic polymer can be selected, for example, from thegroup consisting of homopolymer of N-vinyl lactam, copolymer of N-vinyllactam, cellulose ester, cellulose ether, polyalkylene oxide,polyacrylate, polymethacrylate, polyacrylamide, polyvinyl alcohol, vinylacetate polymer, oligosaccharide, and polysaccharide. As a non-limitingexample, the hydrophilic polymer is selected from the group consistingof homopolymer of N-vinyl pyrrolidone, copolymer of N-vinyl pyrrolidone,copolymer of N-vinyl pyrrolidone and vinyl acetate, copolymer of N-vinylpyrrolidone and vinyl propionate, polyvinylpyrrolidone, methylcellulose,ethylcellulose, hydroxyalkylcelluloses, hydroxypropylcellulose,hydroxyalkylalkylcellulose, hydroxypropylmethylcellulose, cellulosephthalate, cellulose succinate, cellulose acetate phthalate,hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulosesuccinate, hydroxypropylmethylcellulose acetate succinate, polyethyleneoxide, polypropylene oxide, copolymer of ethylene oxide and propyleneoxide, methacrylic acid/ethyl acrylate copolymer, methacrylicacid/methyl methacrylate copolymer, butylmethacrylate/2-dimethylaminoethyl methacrylate copolymer,poly(hydroxyalkyl acrylate), poly(hydroxyalkyl methacrylate), copolymerof vinyl acetate and crotonic acid, partially hydrolyzed polyvinylacetate, carrageenan, galactomannan, and xanthan gum. Preferably, thehydrophilic polymer is selected from polyvinylpyrrolidone (PVP) K17, PVPK25, PVP K30, PVP K90, hydroxypropyl methylcellulose (HPMC) E3, HPMC E5,HPMC E6, HPMC E15, HPMC K3, HPMC A4, HPMC A15, HPMC acetate succinate(AS) LF, HPMC AS MF, HPMC AS HF, HPMC AS LG, HPMC AS MG, HPMC AS HG,HPMC phthalate (P) 50, HPMC P 55, Ethocel 4, Ethocel 7, Ethocel 10,Ethocel 14, Ethocel 20, copovidone (vinylpyrrolidone-vinyl acetatecopolymer 60/40), polyvinyl acetate, methacrylate/methacrylic acidcopolymer (Eudragit) L100-55, Eudragit L100, Eudragit S100, polyethyleneglycol (PEG) 400, PEG 600, PEG 1450, PEG 3350, PEG 4000, PEG 6000, PEG8000, poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, orpoloxamer 407. More preferably, the hydrophilic polymer is selected fromhomopolymers of vinylpyrrolidone (e.g., PVP with Fikentscher K values offrom 12 to 100, or PVP with Fikentscher K values of from 17 to 30), orcopolymers of 30 to 70% by weight of N-vinylpyrrolidone (VP) and 70 to30% by weight of vinyl acetate (VA) (e.g., a copolymer of 60% by weightVP and 40% by weight VA). The surfactant can be selected, for example,from the group consisting of polyoxyethyleneglycerol triricinoleate orpolyoxyl 35 castor oil (Cremophor® EL; BASF Corp.) orpolyoxyethyleneglycerol oxystearate, mono fatty acid ester ofpolyoxyethylene sorbitan, polyoxyethylene alkyl ether, polyoxyethylenealkylaryl ether, polyethylene glycol fatty acid ester, alkylene glycolfatty acid mono ester, sucrose fatty acid ester, and sorbitan fatty acidmono ester. As a non-limited example, the surfactant is selected fromthe group consisting of polyethylenglycol 40 hydrogenated castor oil(Cremophor® RH 40, also known as polyoxyl 40 hydrogenated castor oil ormacrogolglycerol hydroxystearate), polyethylenglycol 60 hydrogenatedcastor oil (Cremophor® RH 60), a mono fatty acid ester ofpolyoxyethylene (20) sorbitan (e.g. polyoxyethylene (20) sorbitanmonooleate (Tween® 80), polyoxyethylene (20) sorbitan monostearate(Tween® 60), polyoxyethylene (20) sorbitan monopalmitate (Tween® 40), orpolyoxyethylene (20) sorbitan monolaurate (Tween® 20)), polyoxyethylene(3) lauryl ether, polyoxyethylene (5) cetyl ether, polyoxyethylene (2)stearyl ether, polyoxyethylene (5) stearyl ether, polyoxyethylene (2)nonylphenyl ether, polyoxyethylene (3) nonylphenyl ether,polyoxyethylene (4) nonylphenyl ether, polyoxyethylene (3) octylphenylether, PEG-200 monolaurate, PEG-200 dilaurate, PEG-300 dilaurate,PEG-400 dilaurate, PEG-300 distearate, PEG-300 dioleate, propyleneglycol monolaurate, sucrose monostearate, sucrose distearate, sucrosemonolaurate, sucrose dilaurate, sorbitan monolaurate, sorbitanmonooleate, sorbitan monopalnitate, and sorbitan stearate. Preferably,the surfactant is selected from polysorbate 20, polysorbate 40,polysorbate 60, polysorbate 80, Cremophor RH 40, Cremophor EL, Gelucire44/14, Gelucire 50/13, D-alpha-tocopheryl polyethylene glycol 1000succinate (vitamin E TPGS), propylene glycol laurate, sodium laurylsulfate, or sorbitan monolaurate. More preferably, the surfactant isselected from sorbitan monolaurate or D-alpha-tocopheryl polyethyleneglycol 1000 succinate.

In another embodiment, a process of the invention comprises dissolving acrystalline form of the invention, a hydrophilic polymer describedabove, and a surfactant described above to form a solution (e.g., amelt). The hydrophilic polymer is a homopolymer or copolymer of N-vinylpyrrolidone (e.g., copovidone). The pharmaceutically acceptablesurfactant can be, e.g., vitamin E TPGS, or sorbitan monolaurate.

A melt-extrusion process of the invention typically comprises preparinga melt from (1) a crystalline form of the invention, (2) a hydrophilicpolymer described above (or another suitable binder), and (3) preferablya surfactant described above. The melt can then be cooled until itsolidifies. The crystalline form of Compound I initially used willdisappear upon the formation of the melt. The melt may also includeother additives. “Melting” means a transition into a liquid or rubberystate in which it is possible for one component to get embedded,preferably homogeneously embedded, in the other component or components.In many cases, the polymer component will melt and the other componentsincluding the crystalline form of Compound I and the surfactant willdissolve in the melt thereby forming a solution. Melting usuallyinvolves heating above the softening point of the polymer. Thepreparation of the melt can take place in a variety of ways. The mixingof the components can take place before, during or after the formationof the melt. For example, the components can be mixed first and thenmelted or be simultaneously mixed and melted. The melt can also behomogenized in order to disperse Compound I efficiently. In addition, itmay be convenient first to melt the polymer and then to mix in andhomogenize Compound I. In one example, all materials except thesurfactant are blended and fed into an extruder, while the surfactant ismolten externally and pumped in during extrusion.

In another example, the melt comprises Compound I and a hydrophilicpolymer described above, and the melt temperature is in the range offrom 100 to 170° C., preferably from 120 to 150° C., and highlypreferably from 135 to 140° C. The melt can also include apharmaceutically acceptable surfactant described above.

In still another example, the melt comprises Compound I, at leastanother anti-HCV agent (e.g., a HCV polymerase inhibitor, or a NS5Ainhibitor, or a combination of a HCV polymerase inhibitor and a NS5Ainhibitor), and a hydrophilic polymer described above. The melt can alsoinclude a pharmaceutically acceptable surfactant described above.

To start a melt-extrusion process, Compound I is employed in acrystalline form of the invention, e.g., any crystalline form describedin any aspect, embodiment or example of this application. A crystallineform of the invention may also be first dissolved in a suitable liquidsolvent such as alcohols, aliphatic hydrocarbons, esters or, in somecases, liquid carbon dioxide; the solvent can be removed, e.g.evaporated, upon preparation of the melt.

Various additives can also be included in the melt, for example, flowregulators (e.g., colloidal silica), lubricants, fillers, disintegrants,plasticizers, colorants, or stabilizers (e.g., antioxidants, lightstabilizers, radical scavengers, and stabilizers against microbialattack).

The melting and/or mixing can take place in an apparatus customary forthis purpose. Particularly suitable ones are extruders or kneaders.Suitable extruders include single screw extruders, intermeshing screwextruders or multiscrew extruders, preferably twin screw extruders,which can be corotating or counterrotating and, optionally, be equippedwith kneading disks. It will be appreciated that the workingtemperatures will be determined by the kind of extruder or the kind ofconfiguration within the extruder that is used. Part of the energyneeded to melt, mix and dissolve the components in the extruder can beprovided by heating elements. However, the friction and shearing of thematerial in the extruder may also provide a substantial amount of energyto the mixture and aid in the formation of a homogeneous melt of thecomponents.

The melt can range from thin to pasty to viscous. Shaping of theextrudate can be conveniently carried out by a calender with twocounter-rotating rollers with mutually matching depressions on theirsurface. The extrudate can be cooled and allow to solidify. Theextrudate can also be cut into pieces, either before (hot-cut) or aftersolidification (cold-cut).

The solidified extrusion product can be further milled, ground orotherwise reduced to granules. The solidified extrudate, as well as eachgranule produced, comprises a solid dispersion, preferably a solidsolution, of Compound I in a matrix comprised of the hydrophilic polymerand optionally the pharmaceutically acceptable surfactant. Where thegranules do not contain any surfactant, a pharmaceutically acceptablesurfactant described above can be added to and blended with thegranules. The extrusion product can also be blended with other activeingredient(s) (e.g., ritonavir) and/or additive(s) before being milledor ground to granules. The granules can be further processed intosuitable solid oral dosage forms.

In one example, copovidone and a surfactant described above are mixedand granulated, followed by the addition of aerosil and a crystallineform of Compound I of the invention. The mixture can also containritonavir. The mixture, which may contain for example 5% by weight ofCompound I, is then milled. The mixture is then subject to extrusion,and the extrudate thus produced can be milled and sieved for furtherprocessing to make capsules or tablets. The surfactant employed in thisexample can also be added through liquid dosing during extrusion.

The approach of solvent evaporation, e.g., via spray-drying, providesthe advantage of allowing for processability at lower temperatures, ifneeded, and allows for other modifications to the process in order tofurther improve powder properties. The spray-dried powder can then beformulated further, if needed, and final drug product is flexible withregards to whether capsule, tablet or any other solid dosage form isdesired.

Exemplary spray-drying processes and spray-drying equipment aredescribed in K. Masters, SPRAY DRYING HANDBOOK (Halstead Press, NewYork, 4^(th) ed., 1985). Non-limiting examples of spray-drying devicesthat are suitable for the present invention include spray dryersmanufactured by Niro Inc. or GEA Process Engineering Inc., BuchiLabortechnik AG, and Spray Drying Systems, Inc. A spray-drying processgenerally involves breaking up a liquid mixture into small droplets andrapidly removing solvent from the droplets in a container (spray dryingapparatus) where there is a strong driving force for evaporation ofsolvent from the droplets. Atomization techniques include, for example,two-fluid or pressure nozzles, or rotary atomizers. The strong drivingforce for solvent evaporation can be provided, for example, bymaintaining the partial pressure of solvent in the spray dryingapparatus well below the vapor pressure of the solvent at thetemperatures of the drying droplets. This may be accomplished by either(1) maintaining the pressure in the spray drying apparatus at a partialvacuum; (2) mixing the liquid droplets with a warm drying gas (e.g.,heated nitrogen); or (3) both.

The temperature and flow rate of the drying gas, as well as the spraydryer design, can be selected so that the droplets are dry enough by thetime they reach the wall of the apparatus. This help to ensure that thedried droplets are essentially solid and can form a fine powder and donot stick to the apparatus wall. The spray-dried product can becollected by removing the material manually, pneumatically, mechanicallyor by other suitable means. The actual length of time to achieve thepreferred level of dryness depends on the size of the droplets, theformulation, and spray dryer operation. Following the solidification,the solid powder may stay in the spray drying chamber for additionaltime (e.g., 5-60 seconds) to further evaporate solvent from the solidpowder. The final solvent content in the solid dispersion as it exitsthe dryer is preferably at a sufficiently low level so as to improve thestability of the final product. For instance, the residual solventcontent of the spray-dried powder can be less than 2% by weight. Highlypreferably, the residual solvent content is within the limits set forthin the International Conference on Harmonization (ICH) Guidelines. Inaddition, it may be useful to subject the spray-dried composition tofurther drying to lower the residual solvent to even lower levels.Methods to further lower solvent levels include, but are not limited to,fluid bed drying, infra-red drying, tumble drying, vacuum drying, andcombinations of these and other processes.

Like the solid extrudate described above, the spray dried productcontains a solid dispersion, preferably a solid solution, of Compound Iin a matrix comprised of a hydrophilic polymer described above andoptionally a pharmaceutically acceptable surfactant described above.Where the spray dried product does not contain any surfactant, apharmaceutically acceptable surfactant described above can be added toand blended with the spray-dried product before further processing.

Before feeding into a spray dryer, a crystalline form of Compound I ofthe invention, a hydrophilic polymer described above, as well as otheroptional active ingredients or excipients such as a pharmaceuticallyacceptable surfactant described above, can be dissolved in a solvent.Suitable solvents include, but are not limited to, alkanols (e.g.,methanol, ethanol, 1-propanol, 2-propanol or mixtures thereof), acetone,acetone/water, alkanol/water mixtures (e.g., ethanol/water mixtures), orcombinations thereof. The solution can also be preheated before beingfed into the spray dryer. In many cases, ritonavir is dissolved togetherwith the crystalline form of Compound I.

The solid dispersion produced by melt-extrusion, spray-drying or othertechniques can be prepared into any suitable solid oral dosage forms. Inone embodiment, the solid dispersion prepared by melt-extrusion,spray-drying or other techniques (e.g., the extrudate or the spray-driedpowder) can be compressed into tablets. The solid dispersion can beeither directly compressed, or milled or ground to granules or powdersbefore compression. Compression can be done in a tablet press, such asin a steel die between two moving punches. When a solid compositioncomprises Compound I and another anti-HCV agent, it is possible toseparately prepare solid dispersions of each individual activeingredient and then blend the optionally milled or ground soliddispersions before compacting. Compound I and another anti-HCV agent canalso be prepared in the same solid dispersion, optionally milled and/orblended with other additives, and then compressed into tablets.Likewise, when a solid composition comprises Compound I and ritonavir,it is possible to separately prepare solid dispersions of eachindividual active ingredient and then blend the optionally milled orground solid dispersions before compacting. Compound I and ritonavir canalso be prepared in the same solid dispersion, optionally milled and/orblended with other additives, and then compressed into tablets.

At least one additive, such as one selected from flow regulators,lubricants, fillers, disintegrants or plasticizers, may be used incompressing the solid dispersion. These additives can be mixed withground or milled solid dispersion before compacting. Disintegrantspromote a rapid disintegration of the compact in the stomach and keepsthe liberated granules separate from one another. Non-limiting examplesof suitable disintegrants are cross-linked polymers such as cross-linkedpolyvinyl pyrrolidone, cross-linked sodium carboxymethylcellulose orsodium croscarmellose. Non-limiting examples of suitable fillers (alsoreferred to as bulking agents) are lactose monohydrate, calciumhydrogenphosphate, microcrystalline cellulose (e.g., Avicell),silicates, in particular silicium dioxide, magnesium oxide, talc, potatoor corn starch, isomalt, or polyvinyl alcohol. Non-limiting examples ofsuitable flow regulators include highly dispersed silica (e.g.,colloidal silica such as Aerosil), and animal or vegetable fats orwaxes. Non-limiting examples of suitable lubricants include polyethyleneglycol (e.g., having a molecular weight of from 1000 to 6000), magnesiumand calcium stearates, sodium stearyl fumarate, and the like.

Various other additives may also be used in preparing a solidcomposition prepared according to a process of the invention, forexample dyes such as azo dyes, organic or inorganic pigments such asaluminium oxide or titanium dioxide, or dyes of natural origin;stabilizers such as antioxidants, light stabilizers, radical scavengers,stabilizers against microbial attack.

In one embodiment, a process of the invention described above (includingany process described in any aspect, embodiment, example or preference)uses a crystalline form of Compound I which has characteristic peaks inthe powder X-ray diffraction (PXRD) pattern as shown in FIG. 1 and whichis substantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 1 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 3.78, 4.09, 8.19, 9.15, 10.42, 13.02,13.50, 18.45, 19.48, and 20.86, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 3.78, 4.09, 6.92, 8.19, 9.15, 10.12,10.42, 12.30, 13.02, 13.50, 14.77, 16.20, 16.97, 18.12, 18.45, 19.48,20.86, 24.24, 24.79, and 25.97, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 3.78, 4.09, 6.72, 6.92, 8.19, 9.15, 9.84,10.12, 10.42, 10.72, 11.66, 12.30, 13.02, 13.50, 14.77, 15.26, 15.62,16.20, 16.97, 17.27, 17.55, 18.12, 18.45, 19.48, 19.90, 20.37, 20.61,20.86, 21.99, 22.25, 22.72, 24.24, 24.79, 25.97, 26.88, 27.42, 27.81,and 30.23, and which is substantially pure. For example, the crystallineform used can be at least 90% pure, preferably at least 95% pure, ormore preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 2 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 2 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.70, 7.53, 10.51, 11.43, 11.80, 15.85,17.23, 19.11, 21.37, and 23.00, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.23, 5.70, 7.53, 8.24, 8.97, 10.51,11.43, 11.80, 12.05, 12.69, 13.23, 14.97, 15.85, 17.23, 19.11, 20.20,21.37, 21.99, 22.22, and 23.00, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.23, 5.70, 7.53, 8.24, 8.97, 10.51,11.43, 11.80, 12.05, 12.69, 13.23, 13.99, 14.97, 15.85, 17.23, 18.45,19.11, 19.76, 20.20, 21.37, 21.99, 22.22, 23.00, 25.17, 25.43, 26.73,and 32.46, and which is substantially pure. For example, the crystallineform used can be at least 90% pure, preferably at least 95% pure, ormore preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 3 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 3 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.22, 5.69, 7.55, 10.49, 11.38, 11.84,15.99, 17.23, 19.18, and 21.41, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.22, 5.69, 7.55, 8.21, 9.40, 10.49,11.38, 11.84, 12.04, 12.67, 13.24, 15.99, 17.23, 19.18, 20.15, 21.41,22.10, 22.53, 23.02, and 25.19, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.22, 5.69, 7.55, 8.21, 8.99, 9.40, 10.49,11.07, 11.38, 11.84, 12.04, 12.67, 13.24, 13.99, 14.96, 15.99, 17.23,18.10, 18.47, 19.18, 20.15, 21.41, 22.10, 22.53, 23.02, 25.19, 25.69,26.57, 26.98, 30.09, and 32.45, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 4 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 4 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.43, 6.24, 7.53, 10.91, 12.34, 12.57,13.67, 13.94, 17.44, and 19.30, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.43, 6.24, 7.53, 8.68, 10.58, 10.91,12.34, 12.57, 13.67, 13.94, 14.71, 15.40, 15.99, 16.64, 17.44, 19.30,19.70, 21.10, 21.33, and 21.72, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.43, 6.24, 7.53, 8.68, 9.28, 10.58,10.91, 11.65, 12.34, 12.57, 13.67, 13.94, 14.71, 15.40, 15.99, 16.64,17.44, 19.30, 19.70, 21.10, 21.33, 21.72, and 22.78, and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 5 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 5 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.57, 6.19, 7.50, 10.86, 11.46, 12.42,13.59, 15.28, 16.66, and 19.44, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.57, 6.19, 7.50, 8.75, 10.86, 11.08,11.46, 12.42, 13.59, 15.28, 16.26, 16.66, 17.25, 17.87, 19.44, 20.80,21.13, 21.39, 22.15, and 27.12, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.57, 6.19, 7.50, 8.75, 10.86, 11.08,11.46, 12.42, 12.84, 13.59, 15.28, 16.26, 16.66, 17.25, 17.87, 19.44,20.80, 21.13, 21.39, 22.15, 23.17, 24.15, and 27.12, and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 6 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 6 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 4.35, 4.68, 7.33, 12.01, 13.13, 13.35,16.54, 17.96, 18.26, and 21.21, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 4.35, 4.68, 6.41, 7.33, 9.54, 10.26,11.13, 11.34, 12.01, 13.13, 13.35, 14.33, 16.54, 17.96, 18.26, 18.60,19.77, 21.21, 21.75, and 24.19, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 4.35, 4.68, 6.41, 6.92, 7.33, 9.25, 9.54,10.26, 11.13, 11.34, 12.01, 13.13, 13.35, 14.33, 14.65, 15.36, 16.54,17.96, 18.26, 18.60, 19.05, 19.77, 21.21, 21.75, and 24.19, and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 7 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 7 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.36, 8.81, 10.09, 10.69, 11.43, 12.95,14.14, 17.96, 18.28, and 22.88, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 3.50, 5.36, 8.81, 10.09, 10.69, 11.43,12.19, 12.95, 14.14, 14.72, 15.18, 17.53, 17.96, 18.28, 18.86, 21.36,22.01, 22.88, 26.54, and 28.04, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 3.50, 4.61, 5.36, 5.79, 7.61, 8.81, 10.09,10.69, 11.43, 12.19, 12.95, 14.14, 14.72, 15.18, 15.64, 16.87, 17.53,17.96, 18.28, 18.86, 19.76, 21.36, 22.01, 22.88, 24.42, 25.20, 26.54,28.04, and 28.65, and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 8 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 8 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.08, 10.81, 12.05, 13.47, 13.68, 17.68,19.02, 19.48, 21.73, and 25.53, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.08, 7.82, 10.27, 10.81, 12.05, 13.47,13.68, 14.95, 16.81, 17.68, 19.02, 19.48, 20.36, 21.73, 22.24, 23.48,25.53, 26.93, 32.01, and 33.12, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.08, 7.82, 10.27, 10.81, 11.11, 12.05,13.47, 13.68, 14.95, 15.57, 16.28, 16.81, 17.68, 19.02, 19.48, 20.36,21.73, 22.24, 23.48, 24.16, 25.53, 26.93, 28.26, 30.41, 31.07, 32.01,33.12, and 35.04, and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 9 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 9 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.31, 11.11, 12.60, 13.75, 15.29, 15.96,17.62, 19.71, 21.30, and 22.88, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75,15.29, 15.96, 17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40, 22.88,23.66, 26.40, 26.74, and 33.46, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.31, 10.16, 10.62, 11.11, 12.60, 13.75,15.29, 15.96, 17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40, 22.88,23.66, 26.40, 26.74, 28.12, 31.62, and 33.46, and which is substantiallypure. For example, the crystalline form used can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern asshown in FIG. 10 and which is substantially pure. For example, thecrystalline form used can be at least 90% pure, preferably at least 95%pure, or more preferably at least 97%.

In yet another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) as shown in Table 10 and which issubstantially pure. For example, the crystalline form used can be atleast 90% pure, preferably at least 95% pure, or more preferably atleast 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 7.42, 10.57, 11.84, 13.74, 15.72, 17.36,19.38, 21.34, 22.07, and 23.36, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.28, 5.65, 7.42, 9.26, 10.57, 10.90,11.31, 11.84, 12.15, 12.73, 13.74, 15.72, 17.36, 18.04, 19.38, 21.34,22.07, 22.90, 23.36, and 26.49, and which is substantially pure. Forexample, the crystalline form used can be at least 90% pure, preferablyat least 95% pure, or more preferably at least 97%.

In another embodiment, a process of the invention described above(including any process described in any aspect, embodiment, example orpreference) uses a crystalline form of Compound I which hascharacteristic peaks in the powder X-ray diffraction (PXRD) pattern atvalues of two theta (° 2θ) of 5.28, 5.65, 7.42, 8.02, 8.94, 9.26, 10.57,10.90, 11.31, 11.84, 12.15, 12.73, 13.14, 13.74, 14.78, 15.72, 16.32,16.95, 17.36, 18.04, 18.81, 19.38, 21.34, 22.07, 22.90, 23.36, 24.50,25.13, 25.59, 26.49, 32.24, and 32.93, and which is substantially pure.For example, the crystalline form used can be at least 90% pure,preferably at least 95% pure, or more preferably at least 97%.

In yet another aspect, the present invention features compositionscomprising a crystalline form of Compound I of the invention. Anycrystalline form described herein (including any crystalline formdescribed in any aspect, embodiment or example) can be used to make acomposition of the invention. Preferably, the crystalline form issubstantially pure, such as at least 90% pure, preferably at least 95%pure, or more preferably at least 97% pure. In one embodiment, acomposition of the invention comprises at least 5% by weight of asubstantially pure crystalline form of the invention. In anotherembodiment, the composition of the invention comprises at least 10% byweight of a substantially pure crystalline form of the invention. Instill another embodiment, a composition of the invention comprises atleast 5% by weight of one or more crystalline forms of the invention. Inyet another embodiment, a composition of the invention comprises atleast 10% by weight of one or more crystalline forms of the invention.

Example 1 Preparation of n-Butylamine-H₂O Solvate (Compound I Pattern A)

Amorphous Compound I was suspended in n-butylamine at ambienttemperature. Solids were isolated after crystallization and left atambient conditions for a short period of time prior to characterization.

The crystal structure has been resolved by Single-Crystal XRD. Theasymmetric unit contains 4 molecules of n-butylamine, 2 molecules ofwater and 2 molecules of Compound I. The experimental powder X-raydiffraction patterns (PXRD) are shown in FIG. 1. Peak listing of theexperimental PXRD pattern with relative intensities is given in Table 1.

Several isostructural crystal forms have been obtained from othersolvents (e.g., propylamine/H2O, amylamine, n-hexylamine,sec-butylamine/H2O, isobutylamine/H2O, n-butanol/Heptane,2-butanol/Heptane, n-pentanol/Heptane, EtOH/Pentane, andn-propanol/Pentane) exhibiting very similar experimental PXRD patterns.These crystal forms are labeled “Pattern A” or “Form I” according totheir PXRD patterns.

Compound I was initially found to be very difficult to crystallizeduring early development. Of all the numerous solvent systemsinvestigated, it was unexpected found that only the n-alkylamines (4-6carbons) led to significant crystallization.

TABLE 1 PXRD Peak Listing of Compound I Pattern A (n-Butylamine-H2OSolvate) Peak Position (° 2θ) Relative Intensity 3.775 64.6 4.087 316.718 11.5 6.921 24.2 8.19 100 9.151 35.7 9.836 12.3 10.118 22.4 10.41960.6 10.724 12.4 11.658 12.9 12.304 20.3 13.019 39.7 13.502 37.3 14.77223.2 15.255 11.7 15.622 7.6 16.196 20.9 16.974 19.1 17.271 12.5 17.54818.4 18.122 19.7 18.445 50.5 19.478 46.5 19.896 11.4 20.371 11.1 20.60918.3 20.861 41.4 21.993 18 22.248 9.2 22.724 8.4 24.242 26.5 24.792 26.625.967 24.1 26.884 6.3 27.415 6.3 27.812 7 30.226 9.5

Example 2 Compound I Pattern B Isolated from MEK/Heptane

Amorphous Compound I was dissolved in methyl ethyl ketone (MEK) atambient temperature and heptane was added. A seed mixture was preparedfrom different crystalline solids of Compound I including Form I(n-butylamine-H2O solvate) and other Pattern A forms isolated fromalkylamines. Solids were isolated after crystallization and left atambient conditions for a short period of time prior to characterization.

Powder X-ray diffraction pattern and peak listing with relativeintensities are shown in FIG. 2 and Table 2, respectively.

TABLE 2 PXRD Peak Listing of Compound I Pattern B (MEK-Heptane Solvate)Peak Position (° 2θ) Relative Intensity 5.228 34.9 5.7 48.7 7.525 628.236 32.7 8.97 27.6 10.514 53.8 11.43 51.9 11.801 51.1 12.053 41.112.689 33.6 13.227 20.6 13.988 20.5 14.973 23.8 15.847 47.1 17.228 64.218.449 15.6 19.114 45.4 19.755 13.8 20.195 34.3 21.367 100 21.988 25.822.217 28 23.003 43.5 25.165 19.7 25.432 13.5 26.726 20 32.455 11.6

Example 3 Compound I Pattern B Isolated from MeOH/Diethyl Ether

Amorphous Compound I was dissolved in methanol at ambient temperatureand diethyl ether was added. Pattern B seeds were added to the solution.Solids were isolated after crystallization and left at ambientconditions for a short period of time prior to characterization.

Powder X-ray diffraction pattern and peak listing with relativeintensities are shown in FIG. 3 and Table 3, respectively.

TABLE 3 PXRD Peak Listing of Compound I Pattern B (MeOH-Diethyl EtherSolvate) Peak Position (° 2θ) Relative Intensity 5.219 55.1 5.686 82.87.545 63.4 8.213 51.9 8.99 18.9 9.399 19 10.491 100 11.068 15.6 11.38477.3 11.841 59.3 12.044 34.4 12.671 35.4 13.243 25.1 13.987 18.3 14.95516 15.985 67.5 17.226 78.1 18.098 11.1 18.47 17.3 19.176 61.2 20.147 3721.409 71.1 22.1 24 22.525 19.8 23.021 41.6 25.188 27.8 25.687 10.626.568 13.9 26.978 18.1 30.091 12.9 32.453 11.7

Several other isostructural Pattern B solvates have also been obtainedfrom >15 solvent systems, which have similar PXRD patterns.

Example 4 Compound 1 Anhydrate (Pattern C)

Compound I Pattern B solvate isolated from methanol and diethyl etherwas dried under vacuum at 50° C. for two weeks. Solids were equilibrateda short time prior to characterization. Powder X-ray diffraction patternand peak listing with relative intensities are shown in FIG. 4 and Table4, respectively.

TABLE 4 PXRD Peak Listing of Compound I Anhydrate (Pattern C) PeakPosition (° 2θ) Relative Intensity 5.433 100 6.239 81.8 7.525 52.2 8.68435.7 9.283 15.3 10.582 27.4 10.914 38.5 11.648 20.1 12.34 47.1 12.56848.6 13.674 78.4 13.942 43 14.711 20.6 15.398 30.4 15.993 27.5 16.63736.4 17.44 37.8 19.304 53.3 19.698 28.8 21.102 32.5 21.332 36.7 21.71533.2 22.776 17.1

Example 5 Compound I MTBE Solvate (Pattern C)

Compound I Pattern B MTBE solvate was dried under vacuum at 70° C. fortwo days. Solids were equilibrated a short time prior tocharacterization. Powder X-ray diffraction pattern and peak listing withrelative intensities are shown in FIG. 5 and Table 5, respectively.

TABLE 5 PXRD Peak Listing of Compound I MTBE Solvate (Pattern C) PeakPosition (° 2θ) Relative Intensity 5.571 98 6.19 100 7.498 34 8.746 2210.861 32.1 11.083 22.4 11.458 41.3 12.419 57.2 12.839 11.4 13.59 33.515.275 56 16.261 28 16.655 33 17.25 13.2 17.867 16.9 19.435 76.3 20.79619.4 21.134 21.7 21.39 23.4 22.147 15.9 23.165 12.1 24.147 10.4 27.1214.2

Example 6 Pattern D

Compound I Pattern B MTBE solvate and Pattern C MTBE solvate werecombined and suspended in 20 w % ethanol in H₂O at ambient temperaturefor approximately three weeks. Solids were analyzed by PXRD while stillwet. Powder X-ray diffraction pattern and peak listing with relativeintensities are shown in FIG. 6 and Table 6, respectively.

TABLE 6 PXRD peak Listing of Compound I Pattern D (from EtOH/H₂O) PeakPosition (° 2θ) Relative Intensity 4.347 63.4 4.684 85.5 6.413 24.06.917 15.3 7.331 43.2 9.246 14.9 9.539 17.1 10.261 18.7 11.127 23.111.337 27.3 12.006 60 13.131 79.8 13.354 35.3 14.325 34.3 14.653 1615.359 13.7 16.536 41.1 17.961 100 18.26 37.3 18.604 22.0 19.054 11.419.774 16.4 21.208 49.6 21.754 22.5 24.19 31.3

Example 7 Compound I Hydrate (Pattern E)

Compound I Pattern D was air dried for approximately 2 h. Powder X-raydiffraction pattern and peak listing with relative intensities are shownin FIG. 7 and Table 7, respectively.

TABLE 7 PXRD Peak Listing of Compound I Hydrate (Pattern E) PeakPosition (° 2θ) Relative Intensity 3.495 22.7 4.611 6.6 5.356 75.5 5.78614.3 7.609 8.6 8.806 42.6 10.091 40.1 10.691 40.2 11.428 54.3 12.19327.6 12.945 40.8 14.143 52.6 14.715 20.7 15.179 30.8 15.643 8.2 16.87313.8 17.525 26.1 17.957 100 18.284 41.2 18.86 25.3 19.757 11.5 21.36319.6 22.006 23.7 22.883 34.6 24.423 13.2 25.203 13.9 26.542 21.5 28.03515.4 28.654 11.7

Example 8 Compound I ACN Solvate (Pattern F or Form II)

Compound I Pattern B MTBE solvate was suspended in acetonitrile atambient temperature over four days. Solids were analyzed by PXRD whilestill wet. Powder X-ray diffraction pattern and peak listing withrelative intensities are shown in FIG. 8 and Table 8, respectively.

TABLE 8 PXRD Peak Listing of Compound I ACN solvate (Form II) PeakPosition (° 2θ) Relative Intensity 5.081 100 7.815 5.6 10.274 7.6 10.81218.3 11.108 4.2 12.052 43.6 13.473 17.7 13.683 13.3 14.948 7.1 15.57 2.916.282 3 16.812 8.4 17.684 14.1 19.017 13.9 19.48 17.5 20.358 11.821.733 47.8 22.237 12 23.483 11.4 24.155 3.3 25.529 27.4 26.933 8.928.264 2.7 30.406 2.8 31.074 1.8 32.013 4.8 33.119 4.6 35.037 2.1

Example 9 Compound I ACN Solvate (Pattern F or Form II)

Compound I was dissolved in acetonitrile at 40° C. Di-n-butyl ether wascharged to prepare a 60% di-n-butyl ether/acetonitrile composition, andthe solution was seeded with Form III. The mixture was charged withdi-n-butyl ether to a composition of 83% di-n-butyl ether/acetonitrileand cooled to 25° C. Solids were analyzed by PXRD while still wet.

Example 10 Compound I Anhydrate (Pattern G or Form III)

Compound I ACN solvate (Form II) was air dried at ambient temperaturefor a few minutes. Powder X-ray diffraction pattern and peak listingwith relative intensities are shown in FIG. 9 and Table 9, respectively.

TABLE 9 PXRD Peak Listing of Compound I Anhydrate (Pattern G or FormIII) Peak Position (° 2θ) Relative Intensity 5.313 100 10.162 6.2 10.6236.5 11.108 9 12.603 34.4 13.753 13.7 15.291 6.7 15.961 9.5 17.618 15.818.192 6.7 19.16 3.2 19.71 9 20.579 5.2 21.296 13.5 22.395 4.1 22.8847.6 23.662 3.9 26.402 6.7 26.743 5.3 28.124 2.1 31.621 2.2 33.461 3.2

Example 11 Compound I di-n-Butyl Ether Solvate (Pattern H)

Compound I Pattern G (Form III) and Pattern C solids in an ˜1:1 ratiowere suspended in di-n-butyl ether at 25° C. for about 3 months. Solidswere analyzed by PXRD after a short equilibration time at ambienttemperature. Powder X-ray diffraction pattern and peak listing withrelative intensities are shown in FIG. 10 and Table 10, respectively.

TABLE 10 PXRD Peak Listing of Compound I di-n-Butyl Ether Solvate(Pattern H) Peak Position (° 2θ) Relative Intensity 5.28 32.5 5.649 28.67.421 75.9 8.017 15.9 8.944 15.8 9.259 31.4 10.574 73.4 10.896 31.111.309 30.2 11.837 52.3 12.154 42.4 12.734 34.1 13.144 22.9 13.742 47.814.778 18.4 15.721 100 16.32 22.1 16.947 19.1 17.359 63.2 18.044 2618.806 22 19.382 54.8 21.335 84.6 22.072 45.3 22.9 28.8 23.358 49.924.504 9.4 25.126 17.3 25.591 19.1 26.49 26.2 32.237 10.7 32.934 8.8

The foregoing description of the present invention provides illustrationand description, but is not intended to be exhaustive or to limit theinvention to the precise one disclosed. Modifications and variations arepossible in light of the above teachings or may be acquired frompractice of the invention. Thus, it is noted that the scope of theinvention is defined by the claims and their equivalents.

What is claimed is:
 1. A process for making a pharmaceutical compositioncomprising

comprising dissolving a crystalline form of Compound I in a solvent,wherein said crystalline form has characteristic peaks in PXRD patternas described in one of Tables 1-10 when tested using a diffractometerthat is operated with a copper anode tube at 40 kV and 30 mA and agermanium monochromator to provide monochromatic Cu-K_(α) radiation witha wavelength of 1.54178 Å.
 2. The process of claim 1, wherein saidsolvent is a volatile solvent, and said process further comprises spraydrying the dissolved Compound I to remove the solvent, thereby creatinga solid dispersion comprising amorphous Compound I.
 3. The process ofclaim 1, wherein said solvent is a molten or rubbery polymer, and saidprocess further comprises cooling and solidifying the dissolved CompoundI, thereby creating a solid dispersion comprising amorphous Compound Iand said polymer.
 4. The process of claim 1, wherein said characteristicpeaks in PXRD pattern are as described in Table
 9. 5. The process ofclaim 2, wherein said characteristic peaks in PXRD pattern are asdescribed in Table
 9. 6. The process of claim 3, wherein saidcharacteristic peaks in PXRD pattern are as described in Table
 9. 7. Aprocess for making a pharmaceutical composition comprising Compound I,

comprising dissolving a crystalline form of Compound I in a solvent,wherein said crystalline form has characteristic peaks in PXRD patternas described in one of FIGS. 1-10 when tested using a diffractometerthat is operated with a copper anode tube at 40 kV and 30 mA and agermanium monochromator to provide monochromatic Cu-K_(α) radiation witha wavelength of 1.54178 Å.
 8. The process of claim 7, wherein saidsolvent is a volatile solvent, and said process further comprises spraydrying the dissolved Compound I to remove the solvent, thereby creatinga solid dispersion comprising amorphous Compound I.
 9. The process ofclaim 7, wherein said solvent is a molten or rubbery polymer, and saidprocess further comprises cooling and solidifying the dissolved CompoundI, thereby creating a solid dispersion comprising amorphous Compound Iand said polymer.
 10. The process of claim 7, wherein saidcharacteristic peaks in PXRD pattern are as described in FIG.
 9. 11. Theprocess of claim 8, wherein said characteristic peaks in PXRD patternare as described in FIG.
 9. 12. The process of claim 9, wherein saidcharacteristic peaks in PXRD pattern are as described in FIG.
 9. 13. Aprocess for making a pharmaceutical composition comprising Compound I,

comprising dissolving a crystalline form of Compound I in a solvent,wherein said crystalline form has characteristic peaks in PXRD patternat values of two theta (° 2θ) of 5.31, 11.11, 12.60, 13.75, 15.29,15.96, 17.62, 19.71, 21.30, and 22.88 when tested using a diffractometerthat is operated with a copper anode tube at 40 kV and 30 mA and agermanium monochromator to provide monochromatic Cu-K_(α) radiation witha wavelength of 1.54178 Å.
 14. The process of claim 13, wherein saidsolvent is a volatile solvent, and said process further comprises spraydrying the dissolved Compound I to remove the solvent, thereby creatinga solid dispersion comprising amorphous Compound I.
 15. The process ofclaim 13, wherein said solvent is a molten or rubbery polymer, and saidprocess further comprises cooling and solidifying the dissolved CompoundI, thereby creating a solid dispersion comprising amorphous Compound Iand said polymer.
 16. A process for making a pharmaceutical compositioncomprising Compound I,

comprising dissolving a crystalline form of Compound I in a solvent,wherein said crystalline form has characteristic peaks in PXRD patternat values of two theta (° 2θ) of 5.31, 10.16, 10.62, 11.11, 12.60,13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40,22.88, 23.66, 26.40, 26.74, and 33.46 when tested using a diffractometerthat is operated with a copper anode tube at 40 kV and 30 mA and agermanium monochromator to provide monochromatic Cu-K_(α) radiation witha wavelength of 1.54178 Å.
 17. The process of claim 16, wherein saidsolvent is a volatile solvent, and said process further comprises spraydrying the dissolved Compound I to remove the solvent, thereby creatinga solid dispersion comprising amorphous Compound I.
 18. The process ofclaim 16, wherein said solvent is a molten or rubbery polymer, and saidprocess further comprises cooling and solidifying the dissolved CompoundI, thereby creating a solid dispersion comprising amorphous Compound Iand said polymer.
 19. A process for making a pharmaceutical compositioncomprising Compound I,

comprising dissolving a crystalline form of Compound I in a solvent,wherein said crystalline form has characteristic peaks in PXRD patternat values of two theta (° 2θ) of 5.31, 10.16, 10.62, 11.11, 12.60,13.75, 15.29, 15.96, 17.62, 18.19, 19.16, 19.71, 20.58, 21.30, 22.40,22.88, 23.66, 26.40, 26.74, 28.12, 31.62, and 33.46 when tested using adiffractometer that is operated with a copper anode tube at 40 kV and 30mA and a germanium monochromator to provide monochromatic Cu-K_(α)radiation with a wavelength of 1.54178 Å.
 20. The process of claim 19,wherein said solvent is a volatile solvent, and said process furthercomprises spray drying the dissolved Compound I to remove the solvent,thereby creating a solid dispersion comprising amorphous Compound I. 21.The process of claim 19, wherein said solvent is a molten or rubberypolymer, and said process further comprises cooling and solidifying thedissolved Compound I, thereby creating a solid dispersion comprisingamorphous Compound I and said polymer.